Diabetes Mellitus is one of the most prevalent causes of death by disease in the United States, outranked only by cardiovascular and neoplastic diseases. See Buchwald, Insulin Replacement: Bionic and Natural, Trans. Am. Artif. Inter. Organ, 33:675(1984), and Report of the National Diabetes Advisory Board, NIH Pub. No. 87-137 (1987). Diabetes is also the leading cause of blindness, kidney related diseases, neurological disorders, cardiovascular diseases, and non-accidental amputation of limbs. See Skylar, Complication of diabetes mellitus: Relationship to metabolic disfunction, Diabetes Care, 2:499 (1979); Frier et al., Does hypoglycemia aggravate the complication of diabetes? Lancet, 11:1175 (1985); and Pirart, Diabetes mellitus and its degenerative complications, a prospective study of 4400 patients observed between 1947 and 1973, Diabetes Metab., 3:173 (1977). Good metabolic control of blood glucose has been the goal of diabetic treatment since the discovery of insulin in 1921 by Banting and Best but has been unobtainable for most diabetic patients. Despite improved treatments using daily insulin injections the majority of insulin dependent patients never maintain the metabolic control necessary for avoiding long-term complications.
Alternative approaches to treat Type I Diabetes Mellitus (to replace daily insulin injections) have been investigated to achieve homeostatic blood glucose levels. The principal concept is to design a biofeedback system in which insulin is released in response to glucose concentrations. At least three approaches thus far have been studied. One is a computer-aided insulin pump with an implanted glucose sensor such as described by Selam et al., Devices for insulin administration, Diabetes Care, 13:955 (1990). Another is a glycosylated insulin-bound Concanavalin A system in which glycosylated insulin is released in response to blood glucose levels as described by Brownlee et al., A glucose-controlled insulin delivery system: Semisynthetic insulin bound to lectin, Science, 206:1190 (1979); Kim et al., A self-regulated insulin delivery system, Edited by T. H. Lee and S. Baba, Excerpta Medica, Amsterdam, (1990), pp. 25-32; and Pai et al., Concanavalin A microspheres for a self-regulating insulin delivery system, J. Pharm. Science., (1992), pp. 532-536. Still another approach is the use of immuno-protected islets by an artificial membrane such as reported by Colton et al., Bioengineering in development of the hybrid artificial pancreas, J. Biomech. Eng., 113:152 (1991).
Artificial pancreas or other endocrine glands utilizing microencapsulation and/or semi-permeable membranes are disclosed in several U.S. patents of which Sun et al., U.S. Pat. No. 4,323,457; Lim, U.S. Pat. No. 4,391,909 and Loeb, U.S. Pat. No. 4,378,016 are representative. The Sun et al. patent discloses an artificial endocrine pancreas for intravascular implantation and is not rechargeable. The Lim patent teaches microencapsulation of tissue cells such as islet of Langerhans which are injected into the body and purportedly ingested after expiration of the cell life. The Loeb patent is drawn to an implantable artificial endocrine gland consisting of a hollow housing having inserted therein an envelope containing hormone producing cells, e.g. .beta.-cells. The entire envelope is replaced by removal from the housing and there is no consideration of volume of the artificial gland implant and mass transport properties between two separating membranes, i.e. implant housing and envelope membrane.
Although numerous investigations for the above approaches have been reported, only limited successes has been obtained in animal models. See, for example, Lum et al., Prolonged reversal of diabetic state in NOD Mice by xenografts of microencapsulated rat islets, Diabetes, 40:1511 (1991); and T. Maki et al., Successful treatment of diabetes with the biohybrid artificial pancreas in dogs, Transplantation, 51:43 (1991). Similarly, success in humans has also been restricted. See, for example, Scharp et al., Insulin independence after islet transplantation into type I diabetic patient, Diabetes, 39:515 (1990); and Robertson, Pancreas Transplantation in humans with diabetes mellitus, Diabetes, 40:1085 (1991).
A most desirable approach in the treatment of Diabetes Mellitus would be through a system utilizing viable islets. The allo- or xenografting of islets, either intravascularly or extravascularly demonstrated the most success in terms of longevity. See Maki et al., supra; Lum et al., supra; and Lacy et al., Maintenance of normoglycemia in diabetic mice by subcutaneous xenografts of encapsulated islets, Science, 254:1782 (1991). It was found that extravascular grafting of microencapsulated islets showed a higher success rate in terms of longevity in treating diabetic animals than intravascular transplantation. For the intravascular device, blood contact resulted in thrombosis and fouling of the membrane as reported by Reach, Bioartificial pancreas: Status and bottlenecks, Intern. J. Art. Organs, 13:329 (1990). However, while highly desirable, a true implantable artificial pancreas for long-term human application has not yet been developed.
Examples of encapsulation of mammalian cells for biohybrid artificial organs are shown by Galletti, Bioartificial Organs, Art. Organs, 16:55 (1992) and Sefton et al., Microencapsulation of mammalian cells in a water-insoluble polyacrylate by coextrusion and interfacial precipitation, Biotech. Bioeng. XXIX: 1135 (1987). The development of large-scale cell culture for cell products is taught by Chang, Artificial cells: 35 years, Art. Organs, 16:8 (1992). The information obtained from these investigations stress that the encapsulation material should be nontoxic to the cells and requires different degree of mechanical strength, permeability, and biocompatibility, depending on the cells to be encapsulated and their applications. Historically, alginate-poly(L-Lysine)-alginate complexes have been used as encapsulating materials, especially for a biohybrid artificial pancreas. This system is based on the ionic interaction of polyanion (alginate) and polycation [poly(L-lysine)] to complex around the islets, forming an immuno-protective boundary, and still permitting diffusion of glucose and insulin as shown by Goosen et al., Optimization of microencapsulation parameters: Semipermeable microcapsules as a bioartificial pancreas, Biotech. Bioeng., XXVII:146 (1985).
The treatment of diabetes with peritoneal implants of encapsulated islets in in vivo diabetic models has been reported by several research groups. See, for example, Colton et al., supra; Reach, supra, and Warnock et al., Critical mass of purified islets that induce normoglycemia after implantation into dogs, Diabetes, 37:467 (1988). Their accumulated data from human and animal experiments have determined that the number of islets required to reverse diabetes is up to 5,000 islets/kg. This figure suggests that a 70 kg patient will need .apprxeq.350,000 islets to maintain suitable blood glucose levels. The volume of encapsulated islets (assuming that a mean capsule diameter containing one islet is .apprxeq.500 .mu.m) would be .apprxeq.18 mL, and have a surface area of .apprxeq.2750 cm.sup.2. Therefore, to be clinically applicable, it would be necessary to reduce the volume and surface area of a biohybrid artificial pancreas.
A major consideration for the design of a biohybrid artificial pancreas is to prolong cell survival within the system. In general, peritoneally implanted membrane encapsulated cells have a limited life span. This is probably due to oxygen deficiency and inactivation of the cells by low molecular weight humoral components of the immune system, such as interleukin-1, although the membrane will isolate the entrapped islets from the cellular immune system or high molecular weight cytokines. Once cell lysis occurs, foreign proteins released from the cells will accelerate the attack of cellular immune system. From this perspective, it is essential that the implanted islets in any form (intra- or extravascular graft, entrapped in housing, hollow fiber, or capsule) should be retrievable or replaceable with fresh islets after a certain period of time. Thus far, the approach to islet implantation (free floating encapsulated cells) in the peritoneal cavity has been limited in practical human application in terms of recovery or replacement of cells. It would therefore be desirable to design a self-contained miniaturized implant from which the islets can be replenished after a certain period of time. Such an approach may also allow sampling of the device for evaluating its status during treatment, without operating on or sacrificing the animal. Another advantage of a self-contained device would be the easy retrieval of islets during an emergency.